ALS affects people in middle to late ages, during a time of life where it is common to suffer from more than one health problem, yet there is little understanding of the effect of chronic medical conditions and medication use on susceptibility to ALS. There is mounting concern and recent evidence that certain medical conditions and medications are associated with an increased risk of developing ALS, while other conditions and medications appear to be inversely associated with ALS risk. We propose to investigate the role of hyperlipidemia, diabetes, autoimmune diseases, as well as the drugs used to treat these disorders, as both risk and prognostic factors for ALS. This study has three specific aims: Aim 1, to investigate the association between antecedent medical conditions and the risk of developing ALS; Aim 2, to examine the relationship between certain classes of medication and the risk of developing ALS; and Aim 3, to determine whether medical conditions or medications present at diagnosis of ALS adversely or positively affect survival with ALS. We will assemble a retrospective cohort of Medicare beneficiaries who were continuously enrolled in fee-for-service Medicare (Parts A, B and D) during the years 2006 through 2014. To address aims 1 and 2, we will conduct a nested case-control study to identify newly diagnosed (incident) patients with ALS in this cohort between 2008 and 2014 using a modified version of the case definition algorithm used by the National ALS Registry. We expect to identify 11,000 incident ALS cases. Using incidence density sampling, ten age- and sex-matched controls will be randomly chosen for each case from among Medicare beneficiaries who entered the Medicare cohort in the same year as the case, but had who had no codes for ALS, MND or closely related conditions prior to their matched cases' diagnosis dates. We will use Medicare inpatient, outpatient, and laboratory health claims to document the occurrence of metabolic, cardiovascular, and autoimmune conditions among the study subjects both before and after the diagnosis of ALS. The availability of Part D (pharmaceutical) claims for Medicare beneficiaries from 2006 onward will provide the opportunity to examine the association of commonly used medications with the risk and prognosis of ALS. We will use conditional logistic regression analyses to identify premorbid medical conditions and medications associated with the risk of developing ALS. To address specific aim 3, we will link the data from our incident ALS case group to mortality data and conduct survival analyses to determine whether antecedent medical conditions and medications present at diagnosis are associated with either shortened or prolonged survival with ALS. We will use survival analysis to determine whether there is an association between these conditions/medications and survival with ALS. This study will contribute significantly to the understanding of the role that metabolic factors, hyperlipidemia, cardiovascular disease and autoimmunity play in the etiology and prognosis of ALS, and could lead to the development of new preventive or therapeutic interventions to prolong survival in ALS patients.